The unifying goal of this proposal is to develop efficient synthetic routes to complex antibiotics, structures that would otherwise be inaccessible for study and evaluation. The primary focus of our work is on the synthesis and evaluation of novel tetracycline antibiotics. Toward this end, we will prepare an extraordinary variety of 6-deoxytetracyclines with modified C and D rings, including heterocycles and fused-ring substituents (e.g., pentacyclines). Our existing route to 6- deoxytetracyclines will be refined and scaled, with the goal of developing a route capable of providing grams to kilograms of novel synthetic tetracyclines. More efficient constructions of AB tetracycline precursors will be explored, and the convergent coupling of AB and D-ring precursors to give the ABCD ring system of the tetracyclines will be optimized, again, with a view to developing a scalable, more efficient synthetic route. In addition, we will undertake basic studies to explore the feasibility of a novel macropolycyclization route to produce the new class of antibiotics known as the pyrrocidines.